Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myeloma

Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals

Leukemia volume 21, pages 541–549 (2007)Cite this article

Abstract

The tumoral clone of Waldenström's macroglobulinemia (WM) shows a wide morphological heterogeneity, which ranges from B lymphocytes (BL) to plasma cells (PC). By means of genome-wide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell counterparts from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes downregulated in WM-BL were IL4R, which plays a relevant role in CLL B-cell survival, and BACH2, which participates in the development of class-switched PC. Interestingly, one of the upregulated genes in WM-BL was IL6. A set of four genes was able to discriminate clonal BL from WM and CLL: LEF1 (WNT/β-catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5, which was overexpressed in WM-PC, and IRF4 and BLIMP1, which were underexpressed. In addition, three of the target genes activated by PAX5 – CD79, BLNK and SYK – were upregulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell counterpart.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakas M . Waldenstrom's macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000; 18: 214–226.

    Article  CAS  PubMed  Google Scholar 

  2. Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 2003; 30: 110–115.

    Article  PubMed  Google Scholar 

  3. San Miguel JF, Vidriales MB, Ocio E, Mateo G, Sánchez-Guijo F, Sánchez ML et al. Immunophenotypic analysis of Waldenstrom's macroglobulinemia. Semin Oncol 2003; 30: 187–195.

    Article  CAS  PubMed  Google Scholar 

  4. Ghobrial IM, Gertz MA, Fonseca R . Waldenstrom macroglobulinaemia. Lancet Oncol 2003; 4: 679–685.

    Article  PubMed  Google Scholar 

  5. Avet-Loiseau H, Garand R, Lode L, Robillard N, Bataille R . 14q32 Translocations discriminate IgM multiple myeloma from Waldenstrom's macroglobulinemia. Semin Oncol 2003; 30: 153–155.

    Article  CAS  PubMed  Google Scholar 

  6. Schop RF, Kuehl WM, Van Wier SA, Ahmann GJ, Price-Troska T, Bailey RJ et al. Waldenstrom macroglobulinemia neoplastic cells lack immunoglobulin heavy chain locus translocations but have frequent 6q deletions. Blood 2002; 100: 2996–3001.

    Article  CAS  PubMed  Google Scholar 

  7. Chng WJ, Schop R, Price-Troska T, Ghobrial I, Kay N, Jelinek DF et al. Gene expression profiling of Waldenstrom's macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006; 108: 2755–2763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gutiérrez NC, López-Pérez R, Hernéndez JM, Isidro I, González B, Delgado M et al. Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia. Leukemia 2005; 19: 402–409.

    Article  PubMed  Google Scholar 

  9. Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP . Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 2003; 31: e15.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863–14868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Borg I, Groenen PM . Modern Multidimensional Scaling: Theory and Applications. Springer Verlag: New York, 1997.

    Book  Google Scholar 

  12. Tusher VG, Tibshirani R, Chu G . Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98: 5116–5121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Smyth GK . Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004; 3: Article 3.

    Article  Google Scholar 

  14. Reiner A, Yekutieli D, Benjamini Y . Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 2003; 19: 368–375.

    Article  CAS  PubMed  Google Scholar 

  15. Tibshirani R, Hastie T, Narasimhan B, Chu G . Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci USA 2002; 99: 6567–6572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shaulian E, Karin M . AP-1 in cell proliferation and survival. Oncogene 2001; 20: 2390–2400.

    Article  CAS  PubMed  Google Scholar 

  17. Hock BD, Haring LF, Steinkasserer A, Taylor KG, Patton WN, McKenzie JL . The soluble form of CD83 is present at elevated levels in a number of hematological malignancies. Leuk Res 2004; 28: 237–241.

    Article  CAS  PubMed  Google Scholar 

  18. Ergun S, Kilik N, Ziegeler G, Hansen A, Nollau P, Gotze J et al. CEA-related cell adhesion molecule 1: a potent angiogenic factor and a major effector of vascular endothelial growth factor. Mol Cell 2000; 5: 311–320.

    Article  CAS  PubMed  Google Scholar 

  19. Shapiro-Shelef M, Calame K . Plasma cell differentiation and multiple myeloma. Curr Opin Immunol 2004; 16: 226–234.

    Article  CAS  PubMed  Google Scholar 

  20. Lin P, Mahdavy M, Zhan F, Zhang HZ, Katz RL, Shaughnessy JD . Expression of PAX5 in CD20-positive multiple myeloma assessed by immunohistochemistry and oligonucleotide microarray. Mod Pathol 2004; 17: 1217–1222.

    Article  CAS  PubMed  Google Scholar 

  21. Shapiro-Shelef M, Calame K . Regulation of plasma-cell development. Nat Rev Immunol 2005; 5: 230–242.

    Article  CAS  PubMed  Google Scholar 

  22. Calame KL, Lin KI, Tunyaplin C . Regulatory mechanisms that determine the development and function of plasma cells. Annu Rev Immunol 2003; 21: 205–230.

    Article  CAS  PubMed  Google Scholar 

  23. Richardson SJ, Matthews C, Catherwood MA, Alexander HD, Carey BS, Farrugia J et al. ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). Blood 2006; 107: 3584–3592.

    Article  CAS  PubMed  Google Scholar 

  24. Till KJ, Lin K, Zuzel M, Cawley JC . The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes. Blood 2002; 99: 2977–2984.

    Article  CAS  PubMed  Google Scholar 

  25. Wong S, Fulcher D . Chemokine receptor expression in B-cell lymphoproliferative disorders. Leuk Lymphoma 2004; 45: 2491–2496.

    Article  CAS  PubMed  Google Scholar 

  26. Reya T, Clevers H . Wnt signalling in stem cells and cancer. Nature 2005; 434: 843–850.

    Article  CAS  PubMed  Google Scholar 

  27. Qiang YW, Endo Y, Rubin JS, Rudikoff S . Wnt signaling in B-cell neoplasia. Oncogene 2003; 22: 1536–1545.

    Article  CAS  PubMed  Google Scholar 

  28. Howe D, Bromidge T . Variation of LEF-1 mRNA expression in low-grade B-cell non-Hodgkin's lymphoma. Leuk Res 2006; 30: 29–32.

    Article  CAS  PubMed  Google Scholar 

  29. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM et al. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2004; 101: 3118–3123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hatzimichael EC, Christou L, Bai M, Kolios G, Kefala L, Bourantas KL . Serum levels of IL-6 and its soluble receptor (sIL-6R) in Waldenstrom's macroglobulinemia. Eur J Haematol 2001; 66: 1–6.

    Article  CAS  PubMed  Google Scholar 

  31. Kay NE, Pittner BT . IL-4 biology: impact on normal and leukemic CLL B cells. Leuk Lymphoma 2003; 44: 897–903.

    Article  CAS  PubMed  Google Scholar 

  32. Sakane-Ishikawa E, Nakatsuka S, Tomita Y, Fujita S, Nakamichi I, Takakuwa T et al. Prognostic significance of BACH2 expression in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. J Clin Oncol 2005; 23: 8012–8017.

    Article  CAS  PubMed  Google Scholar 

  33. Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 2004; 429: 566–571.

    Article  CAS  PubMed  Google Scholar 

  34. Mayr C, Bund D, Schlee M, Moosmann A, Kofler DM, Hallek M et al. Fibromodulin as a novel tumor-associated antigen (TAA) in chronic lymphocytic leukemia (CLL), which allows expansion of specific CD8+ autologous T lymphocytes. Blood 2005; 105: 1566–1573.

    Article  CAS  PubMed  Google Scholar 

  35. Mikaelsson E, nesh-Manesh AH, Luppert A, Jeddi-Tehrani M, Rezvany MR, Sharifian RA et al. Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Blood 2005; 105: 4828–4835.

    Article  CAS  PubMed  Google Scholar 

  36. Ek S, Hogerkorp CM, Dictor M, Ehinger M, Borrebaeck CA . Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. Cancer Res 2002; 62: 4398–4405.

    CAS  PubMed  Google Scholar 

  37. Cooper D, Lindberg FP, Gamble JR, Brown EJ, Vadas MA . Transendothelial migration of neutrophils involves integrin-associated protein (CD47). Proc Natl Acad Sci USA 1995; 92: 3978–3982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mateo V, Brown EJ, Biron G, Rubio M, Fischer A, Deist FL et al. Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization. Blood 2002; 100: 2882–2890.

    Article  CAS  PubMed  Google Scholar 

  39. Katayama Y, Sakai A, Oue N, Asaoku H, Otsuki T, Shiomomura T et al. A possible role for the loss of CD27–CD70 interaction in myelomagenesis. Br J Haematol 2003; 120: 223–234.

    Article  CAS  PubMed  Google Scholar 

  40. Prasad KV, Ao Z, Yoon Y, Wu MX, Rizk M, Jacquot S et al. CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein. Proc Natl Acad Sci USA 1997; 94: 6346–6351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 2483–2494.

    Article  CAS  PubMed  Google Scholar 

  42. Liang Y, Tedder TF . Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse. Genomics 2001; 72: 119–127.

    Article  CAS  PubMed  Google Scholar 

  43. Martínez N, Camacho FI, Algara P, Rodríguez A, Dopazo A, Ruiz-Ballesteros E et al. The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. Cancer Res 2003; 63: 8226–8232.

    PubMed  Google Scholar 

  44. Wynn TA . IL-13 effector functions. Annu Rev Immunol 2003; 21: 425–456.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We to thank Mark Anderson from the University Technology Transfer Office, and Isabel Isidro and Teresa Prieto for technical assistance. This study was partially supported by Spanish Myeloma Network Program (G03/136), ‘Ministerio de Ciencia y Tecnología’ grant (SAF 04/06587) and ‘Junta de Castilla y León’ grant (106/A/06).

Author information

Authors and Affiliations

  1. Servicio de Hematología, Hospital Universitario de Salamanca and Centro de Investigación del Cáncer (CIC), Universidad de Salamanca-CSIC, Salamanca, Spain

    N C Gutiérrez, E M Ocio, P Maiso, M Delgado, M J Arcos, J M Hernández & J F San Miguel

  2. Grupo de Investigación Bioinformática, Centro de Investigation del Cáncer (CIC), Universidad de Salamanca-CSIC, Salamanca, Spain

    J de las Rivas

  3. Unidad de Genómica, Centro de Investigation del Cáncer (CIC), Universidad de Salamanca-CSIC, Salamanca, Spain

    E Fermiñán

  4. Servicio General de Citometría, Centro de Investigacion del Cáncer (CIC), Universidad de Salamanca-CSIC, Salamanca, Spain

    M L Sánchez

Authors
  1. N C Gutiérrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E M Ocio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J de las Rivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Maiso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Fermiñán
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M J Arcos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M L Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J M Hernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J F San Miguel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J F San Miguel.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gutiérrez, N., Ocio, E., de las Rivas, J. et al. Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia 21, 541–549 (2007). https://doi.org/10.1038/sj.leu.2404520

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404520

Keywords

This article is cited by

Search

Advanced search

Quick links